MATERNO-FETAL MEDICINE

Hypotension in normotensive pregnant women treatedwith nifedipine as a tocolytic drug

Suchaya Luewan • Rathasart Mahathep •

Theera Tongsong

Received: 6 June 2010 / Accepted: 2 September 2010 / Published online: 16 September 2010

� Springer-Verlag 2010

Abstract

Objective To determine hypotensive effect of nifedipine

in the treatment of preterm labor.

Methods A descriptive analytic study was conducted on

pregnant women treated with nifedipine as tocolytic drug

for preterm labor. Maternal blood pressure before and at

15, 30, 45 and 60 min after administration of nifedipine

was evaluated and analyzed. Hypotension was defined as a

decrease in systolic or diastolic blood pressure of

15 mmHg or more.

Results A total of 157 pregnant women met the inclusion

criteria. The mean systolic and diastolic blood pressure

before treatment was 109.4 and 72.5 mmHg, respectively.

The blood pressure following treatment with nifedipine

was significantly decreased both systolic and diastolic

blood pressure (p \ 0.05) at 30, 45 and 60 min. Of 157

patients, 28 (17.8%) and 27 (17.2%) had systolic and dia-

stolic hypotension, respectively. Of the patients with

decreased blood pressure, the mean decrease of systolic

and diastolic blood pressure was 16.3 and 14.5 mmHg,

respectively.

Conclusion Nifedipine was associated with a minimal but

significant decrease in blood pressure. 17% of cases have

hypotension. However, hypotension secondary to nifedi-

pine was not associated with significant clinical symptoms,

suggesting that nifedipine is relatively safe in terms of

hypotensive effect.

Keywords Maternal hypotension � Nifedipine � Preterm

labor

Introduction

Preterm labor, defined as labor occurring prior to 37 weeks

of gestation which occurs in 6.8–11% of pregnancies

worldwide [1–4]. Preterm birth has been a major cause of

perinatal morbidity and mortality. In preterm labor, tocol-

ysis has been commonly used to prolong pregnancies that

allow corticosteroid administration to promote fetal pul-

monary maturation and thus reduce negative consequences

of preterm birth. Terbutaline (beta-adrenergic agonists) has

been used as a tocolytic drug for a long time. Nevertheless,

many serious side effects are associated with beta-adren-

ergic agonists, such as hypotension, tachycardia, headache,

tremor, nausea, anxiety and disturbances in metabolism

(elevated liver enzymes, hypokalemia, and hyperglycemia)

and maternal pulmonary edema. The beta-adrenergic ago-

nists cause an increase in fetal heart rate and neonatal

hypoglycemia [5–7]. Currently, nifedipine (calcium chan-

nel blocker) has demonstrated similar or even more effi-

cacy with fewer maternal side effects and neonatal

morbidity than beta-adrenergic agonist (terbutaline) [8–12],

resulting in increasing use and becoming more popular

recently. Nifedipine acts to inhibit the entry of calcium

through channels in the cell membrane. Several authors

have found that nifedipine is safer and more effective

tocolytic agent than beta-agonists [10, 13, 14]. However,

though nifedipine is now widely accepted as tocolytic, it

has been developed to treat hypertension and is not aimed

for use in normotensive patients. Therefore, this drug may

potentially be associated with severe hypotension when

used as tocolytic in normal pregnant women. Though

efficacy of nifedipine has been reported several times,

hypotensive effect of nifedipine in normotensive pregnant

women has never been thoroughly studied. The objectives

of this study were to evaluate the hypotensive effects of

S. Luewan (&) � R. Mahathep � T. Tongsong

Department of Obstetrics and Gynecology, Faculty of Medicine,

Chiang Mai University, Chiang Mai 50200, Thailand

e-mail: suleuwan@med.cmu.ac.th

123

Arch Gynecol Obstet (2011) 284:527–530

DOI 10.1007/s00404-010-1674-z

nifedipine administered as a tocolytic agent to normoten-

sive women with preterm labor.

Materials and methods

This prospective descriptive study was conducted at the

Department of Obstetrics and Gynecology, Maharaj Nakorn

Chiang Mai Hospital, Thailand, between 1 January 2004 and

31 December 2008. A total of 161 pregnant women were

included in this study. The inclusion criteria consisted of

normotensive pregnant women who received nifedipine for

tocolytic therapy according to clinical practice guidelines of

Maharaj Nakorn Chiang Mai Hospital and reached the max-

imum loading dose, 40 mg. The clinical practice guidelines

for preterm labor at Maharaj Nakorn Chiang Mai Hospital is a

nifedine as a tocolytic therapy with 10 mg orally for loading

dose, up to 4 doses every 15 min then 4–6 h follow with

maintenance dose of 60 mg (control release) orally for 48 h

or not exceeding 7 days. The main outcome measured was

maternal blood pressure after nifedipine administration.

Maternal blood pressure was recorded before and at 15, 30, 45

and 60 min after first dose of nifedipine. Hypotension was

defined as a decrease in systolic blood pressure (SBP) or

diastolic blood pressure (DBP) of at least 15 mmHg from

baseline blood pressure (before first dose of nifedipine

administration). The exclusion criteria were inability to

follow the practice guideline mentioned above such as

receiving loading dose of nifedipine less than 40 mg,

incomplete medical data, and receiving other medications

which affects nifedipine action such as magnesium sulfate.

Palpitation, headache and other side effects were also pro-

spectively recorded. This study was conducted with approval

of Research Ethics Committee 3, Faculty of medicine, Chiang

Mai University, Chiang Mai, Thailand.

Statistical analysis

The data were analyzed using the statistical package for the

social sciences (SPSS version 15.0). Descriptive data were

presented as mean ± standard deviation, range and

number. Differences in categorical and continuous data

were assessed using the paired t test, respectively. A

p value of 0.05 or lower was considered statistically

significant.

Results

During the study period, a total of 161 pregnant women

were diagnosed for preterm labor and received nifedipine

for tocolytic therapy. Four of them were excluded due to

inability to follow the practice guideline mentioned above.

Finally, 157 cases were finally available for analysis. The

mean maternal age was 28.2 years (range 14–45 years) and

mean gestational age was 29.3 weeks. Eighty-two (52%)

were nulliparous. One hundred and thirty-one (83%)

women had a singleton pregnancy and 26 (17%) were twin

pregnancies.

Before using nifedipine, the mean systolic and diastolic

blood pressures were 109.4 ± 10.4 and 72.5 ± 7.9 mmHg,

respectively. All cases had normal blood pressure and none

of them had blood pressure less than 90/60 mmHg. In

about one-third, blood pressure decreased after receiving

nifedipine. After receiving nifedipine, blood pressure was

decreased, or unchanged in most cases. Surprisingly, in

some cases it was slightly increased. Overall, the systolic

blood pressure was significantly decreased after using

nifedipine at 30, 45 and 60 min (p \ 0.05) and mean

changes of blood pressure were 2.8, 3.3 and 4.5 mmHg,

respectively. Likewise, diastolic blood pressure was

significantly decreased after using nifedipine at 15, 30, 45

and 60 min (p \ 0.05) and mean changes of diastolic blood

pressure were 2.0, 3.1, 4.2 and 4.2 mmHg, respectively, as

shown in Table 1. All cases received a maximum 40 mg of

nifedipine in first hour.

Table 2 shows the rates of patients with hypotension

defined as mentioned above at 15, 30, 45 and 60 min after

nifedipine administration. Nevertheless, hypotension in

most cases occurred in the same patients at various points

of time. The overall rates of patients with systolic and

diastolic hypotension (at least once at any time points) was

Table 1 Changes in blood pressure during the first hour of treatment

Time after treatment (min) Systolic BP Diastolic BP

Mean ± SD

(mmHg)

BP changed from base

line (mmHg) 95% CI

p value* Mean ± SD

(mmHg)

BP changed from base

line (mmHg) 95% CI

p value*

Base line 109.4 ± 10.4 – – 72.5 ± 7.9 – –

15 107.9 ± 10.0 1.4, -0.1–3.1 0.079 70.4 ± 8.3 2.0, 0.6–3.4 0.003**

30 106.6 ± 10.0 2.8, 1.3–4.3 \0.001** 69.3 ± 9.3 3.1,1.5–4.7 \0.001**

45 106.1 ± 9.7 3.3, 1.9–4.8 \0.001** 68.2 ± 8.1 4.2, 2.8–5.7 \0.001**

60 104.9 ± 10.5 4.5, 2.7–6.2 \0.001** 68.3 ± 7.4 4.2, 2.8–5.5 \0.001**

* By the paired t test, ** p value \ 0.05

528 Arch Gynecol Obstet (2011) 284:527–530

123

28 (17.8%) and 27 (17.2%) out of 157, respectively. Of

patients with decreased blood pressure, the mean decrease

of systolic and diastolic blood pressure was 16.3 and

14.5 mmHg, respectively. However, none of them had

blood pressure of lower than 80/40 mmHg. When using

absolute definition of hypotension (one or more values of

systolic or diastolic less than 90 or 60 mmHg, respectively,

the incidence of hypotension at 15, 30, 45 and 60 min were

between 0.6 and 3.8% as seen in Table 3 (McNamara Chi-

square test p [ 0.05 at all time points).

Mean baseline maternal heart rate was 89.6 ± 14.8 bpm

and changed significantly after 45 and 60 min of nifedipine

administration, as presented in Table 4. The maximum

level of heart rate was 93.4 ± 12.8 bpm at 45 min after

nifedipine administration. Additionally, none of them had

maternal heart rates more than 120 bpm. Seven of 157

women had minor side effects after treatment including

palpitation in six women (3.82%) and mild headache in one

patient. None of them was intolerant to the side effects.

Discussion

The use of nifedipine has become commonplace in

management of preterm labor. Several relatively small

randomized trials have compared calcium channel blockers

(nifedipine) with beta-agonists and the meta-analyses of

these studies have demonstrated superior or comparable

efficacy of nifedipine and a fewer adverse effects. How-

ever, the safety of calcium channel blockers in pregnancy

has not been rigorously evaluated [15, 16].

Although nifedipine has hypotensive effect for treatment

of hypertension, several studies have demonstrated that

hypotension secondary to nifedipine in normotensive

women treated for preterm labor is minimal and not clin-

ically significant [8, 10, 17]. In some reports, however, this

hypotensive effect can be severe enough to cause fetal

death [18]. To date the safety of nifedipine in the term of

hypotension is yet a subject to be elucidated. Unlike

several studies in which no details of systolic and diastolic

blood pressure were given at different time periods after

drug administration, this study focused on blood pressure at

various time points after receiving nifedipine. As expected,

nevertheless, our results showed that blood pressure was

slightly decreased after nifedipine administration but not

clinically significant in terms of fetal well-being and

maternal symptoms. Only 17% of case had hypotension

within 60 min after receiving nifedipine but no severe

hypotension or fetal death was observed in 157 women.

Notably, most women (more than 80%) had no hypoten-

sion at any recorded time point within 60 min of treatment.

In other words, blood pressure in normotensive women

treated with nifedipine as a tocolytic was unchanged in

most cases. Surprisingly, despite a significant decrease in

both diastolic and systolic blood pressure, no other adverse

effects such as headache, dizziness, nausea or clinical

symptoms of hypotension were observed in most of them.

Although an increase in maternal heart rate also was

commonly found, tachycardia or arrhythmia was not seen

as reported in other previous reports [17, 19]. Only 7 out of

157 had minor adverse effects (palpitation and headache)

and all of them could tolerate such effects. Nevertheless,

the advantage of the study is that it is the largest study

focusing on hypotensive effect. The results of this study

supports that nifedipine can be safely used in preterm birth

without profound hypotension though close monitoring of

vital signs is warranted.

Table 3 Incidence of hypotension (systolic \ 90 mmHg or dia-

stolic \ 60 mmHg) of at least one time at various time points after

first dose of nifedipine

Time points Systolic hypotension Diastolic hypotension

N out of 157 % N out of 157 %

15 min 1 0.6 1 0.6

30 min 1 0.6 5 3.2

45 min 2 1.3 4 2.5

60 min 4 2.5 1 0.6

Total 5 3.2 6 3.8

Compared to the incidence before drug administration with McNa-

mara Chi-square, p [ 0.05 at 15, 30, 45 and 60 min)

Table 4 Changes in heart rate during the first hour of treatment

Time after treatment (min) Heart rate

Mean ± SD

(bpm)

Increased from

base line (bpm)

p value*

Base line 89.6 ± 14.8 – –

15 89.9 ± 12.8 0.3 0.703

30 91.9 ± 12.2 2.3 0.016**

45 93.4 ± 12.8 3.7 \0.001**

60 93.2 ± 13.2 3.6 \0.001**

* By the paired t test, ** p value \ 0.05

Table 2 Incidence of hypotension (systolic and diastolic) within at

various time points after first dose of nifedipine

Time points Systolic hypotension Diastolic hypotension

N out of 157 % N out of 157 %

15 min 17 10.8 12 7.6

30 min 15 9.6 13 8.3

45 min 18 11.5 16 10.2

60 min 24 15.3 15 9.6

Total 28 17.8 27 17.2

Arch Gynecol Obstet (2011) 284:527–530 529

123

The weakness of this study is that the regimen used in

this study was a low-dose one; therefore, the result of

hypotensive effect may not represent the other higher dose

regimens of nifedipine. Additionally, the main outcomes

included only blood pressure measured within 60 min, not

included thereafter or during the maintenance doses since

the dosage after initial phase was usually varied depending

on patients’ response. Therefore, our results can represent

the hypotensive effects of nifedipine only during initial

phase of treatment. Finally, variation of blood pressure

changes may be influenced by other confounding factors

which might have not been perfectly controlled, such as

techniques or position in the measurement.

In conclusion, nifedipine for treatment of preterm labor

in normotensive women was associated with a minimal but

significant decrease in blood pressure with 17% rate of

hypotension. However, hypotension secondary to nifedi-

pine was not associated with significant clinical symptoms.

The present study suggests that nifedipine is relatively safe

in term of hypotensive effect when used as an alternative

tocolytic agent.

Conflict of interest None.

References

1. Allen SR (1991) Epidemiology of premature rupture of the fetal

membranes. Clin Obstet Gynecol 34:685–693

2. Goldenberg RL, Rouse DJ (1998) Prevention of premature birth.

N Engl J Med 339:313–320

3. Martin JA, Hamilton BE, Ventura SJ, Menacker F, Park MM,

Sutton PD (2002) Births: final data for 2001. Natl Vital Stat Rep

51:1–102

4. Powell SL, Holt VL, Hickok DE, Easterling T, Connell FA

(1995) Recent changes in delivery site of low-birth-weight infants

in Washington: impact on birth weight-specific mortality. Am J

Obstet Gynecol 173:1585–1592

5. ACOG practice bulletin (2003) Management of preterm labor.

Number 43, May 2003. Int J Gynaecol Obstet 82:127–135

6. Berkman ND, Thorp JM Jr, Lohr KN, Carey TS, Hartmann KE,

Gavin NI et al (2003) Tocolytic treatment for the management of

preterm labor: a review of the evidence. Am J Obstet Gynecol

188:1648–1659

7. Hannah ME (2000) Search for best tocolytic for preterm labour.

Lancet 356(9231):699–700

8. Bracero LA, Leikin E, Kirshenbaum N, Tejani N (1991) Com-

parison of nifedipine and ritodrine for the treatment of preterm

labor. Am J Perinatol 8:365–369

9. Cararach V, Palacio M, Martinez S, Deulofeu P, Sanchez M,

Cobo T et al (2006) Nifedipine versus ritodrine for suppression of

preterm labor. Comparison of their efficacy and secondary

effects. Eur J Obstet Gynecol Reprod Biol 127:204–208

10. King JF, Flenady V, Papatsonis D, Dekker G, Carbonne B (2003)

Calcium channel blockers for inhibiting preterm labour: a sys-

tematic review of the evidence and a protocol for administration

of nifedipine. Aust N Z J Obstet Gynaecol 43:192–198

11. Raymajhi R, Pratap K (2003) A comparative study between

nifedipine and isoxsuprine in the suppression of preterm labour.

Kathmandu Univ Med J (KUMJ) 1:85–90

12. Weerakul W, Chittacharoen A, Suthutvoravut S (2002) Nifedi-

pine versus terbutaline in management of preterm labor. Int J

Gynaecol Obstet 76:311–313

13. Papatsonis DN, Van Geijn HP, Ader HJ, Lange FM, Bleker OP,

Dekker GA (1997) Nifedipine and ritodrine in the management of

preterm labor: a randomized multicenter trial. Obstet Gynecol

90:230–234

14. Keirse MJ (1995) New perspectives for the effective treatment of

preterm labor. Am J Obstet Gynecol 173:618–628

15. Klam SL, Leduc L (2004) Management options for preterm

labour in Canada. J Obstet Gynaecol Can 26:339–345

16. Mawaldi L, Duminy P, Tamim H (2008) Terbutaline versus

nifedipine for prolongation of pregnancy in patients with preterm

labor. Int J Gynaecol Obstet 100:65–68

17. Laohapojanart N, Soorapan S, Wacharaprechanont T, Ratanaja-

mit C (2007) Safety and efficacy of oral nifedipine versus ter-

butaline injection in preterm labor. J Med Assoc Thai

90:2461–2469

18. Papatsonis DN, Carbonne B, Dekker GA, Flenady V, King JF

(2005) Severe hypotension and fetal death due to tocolysis with

nifedipine. BJOG 112:1582–1583

19. Chan LW, Sahota DS, Yeung SY, Leung TY, Fung TY, Lau TK

et al (2008) Side-effect and vital sign profile of nifedipine as a

tocolytic for preterm labour. Hong Kong Med J 14:267–272

530 Arch Gynecol Obstet (2011) 284:527–530

123

Copyright of Archives of Gynecology & Obstetrics is the property of Springer Science & Business Media B.V.

and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright

holder's express written permission. However, users may print, download, or email articles for individual use.